Processes and intermediates for preparing substituted chromanol derivatives

ABSTRACT

The invention relates to processes for preparing a compound of the formula                    
     and the enantiomer of said compound, wherein the benzoic acid moiety is attached at position 6 or 7 of the chroman ring, and R 1 , R 2 , and R 3  are as defined herein. The invention further relates to intermediates that are useful in the preparation of the compound of formula X above.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 09/511,475filed Feb. 23, 2000 now U.S. Pat. No. 6,288,242, which is a divisionalof U.S. application Ser. No. 09/367,235 filed Mar. 5, 1999 now U.S. Pat.No. 6,096,906, which is the National Stage of International ApplicationNo. PCT/IB97/01024 having an international filing date of Aug. 25, 1997designating inter alia the United States Provisional Application No.60/026,372 which has a priority filing date of Sep. 16, 1996.

BACKGROUND OF THE INVENTION

This invention relates to the preparation of substituted chromanolderivatives and to intermediates useful in said preparation. Thesubstituted chromanol derivatives that are prepared in accord with thepresent invention are disclosed in U.S. patent application Ser. No.08/295,827, filed Jan. 9, 1995, entitled “Benzopyran And Related LTB₄Antagonists,” now U.S. Pat. No. 5,552,435, PCT international applicationpublication number WO 96/11925 (published Apr. 25, 1996), PCTinternational application publication number WO 96/11920 (published Apr.25, 1996), PCT international application publication number WO 93/15066(published Aug. 5,1993). Each of the foregoing United States and PCTinternation patent applications are incorporated herein by reference intheir entirety.

The substituted chromanol derivatives that are prepared in accord withthe present invention inhibit the action of LTB₄, as disclosed in U.S.patent application Ser. No. 08/295,827, referred to above. As LTB₄antagonists, the substituted chromanol derivatives that are preparedaccording to the present invention are useful in the treatment ofLTB₄-induced illnesses such as inflammatory disorders includingrheumatoid arthritis, osteoarthritis, inflammatory bowel disease,psoriasis, eczema, erythma, pruritis, acne, stroke, graft rejection,autoimmune diseases, and asthma.

SUMMARY OF THE INVENTION

The present invention relates to a process of preparing a compound ofthe formula

or the enantiomer of said compound, wherein in said compound of formulaX the R³-substituted benzoic acid moiety is attached at carbon 6 or 7 ofthe chroman ring;

R¹ is —(CH₂)_(q)CHR⁵R⁶ wherein q is 0 to 4;

each R² and R³ is independently selected from the group consisting of H,fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl,phenylsulfonyl, and —S(O)_(n)(C₁-C₆ alkyl) wherein n is 0 to 2, andwherein said alkyl group, the alkyl moiety of said alkoxy and—S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups;

R⁵ is H, C₁-C₆ alkyl, or phenyl substituted by R²;

R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10 memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted by 1 or 2 substituents independently selected from phenyl,R², and phenyl substituted by 1 or 2 R²;

which comprises treating a compound of the formula

or the enantiomer of said compound of formula IX in the preparation ofthe enantiomer of said compound of formula X, wherein R¹, R², and R³ areas defined above, R⁴ is C₁-C₆ alkyl, and the benzoate moiety is attachedto position 6 or 7 of the chroman ring, with a base.

In said process of preparing the compound of formula X, the compound offormula IX is preferably treated with an aqueous hydroxide base, R¹ ispreferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl,4-(4-fluorophenyl)benzyl, or phenethyl, R² is preferably hydrogen orfluoro, R³ is preferably fluoro, chloro, or methyl optionallysubstituted by 1 to 3 fluorines, and R⁴ is preferably ethyl or2,2-dimethylpropyl. Most preferably, said compound of formula IX istreated with a base comprising aqueous sodium hydroxide, said compoundof formula IX is(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester, and said compound of formula X is(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid.

In a further aspect of the present invention, said compound of formulaIX, or the enantiomer of said compound, wherein R¹, R², R³, and R⁴ areas defined above, is prepared by treating a compound of the formula

or the enantiomer of said compound of formula VII in the preparation ofthe enantiomer of the compound of formula IX, wherein R¹ and R² are asdefined above and the boronic acid moiety is attached at position 6 or 7of the chroman ring, with a compound of the formula

wherein R³ and R⁴ are as defined above and Z is halo or C₁-C₄perfluoroalkylsulfonate, in the presence of a base or fluoride salt anda palladium catalyst.

In said process of making the compound of formula IX, or the enantiomerof said compound, preferred substituents for R¹, R², R³ and R⁴ are asstated above for said process of making the compound of formula X. Inanother preferred embodiment, Z is halo, the base or fluoride salt isselected from sodium carbonate, triethylamine, sodium bicarbonate,cesium carbonate, tripotassium phosphate, potassium fluoride, cesiumfluoride, sodium hydroxide, barium hydroxide, and tetrabutylammoniumfluoride, the palladium catalyst is selected fromtetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),and 10% palladium on carbon. Most preferably, the base or fluoride saltis potassium fluoride, the palladium catalyst is 10% palladium oncarbon, the compound of formula VII is(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid, and the compoundof formula VIII is ethyl 2-iodo-4-trifluoromethyl-benzoate.

In a further aspect of the invention, the compound of formula VII, orthe enantiomer of said compound, wherein R¹ and R² are as defined above,is prepared by treating a compound of the formula

or the enantiomer of said compound of formula VI in the preparation ofthe enantiomer of the compound of formula VII, wherein R¹ and R² are asdefined above and X is a halide and is attached at position 6 or 7 ofthe chroman ring, with (1) C₁-C₄ alkyl lithium, and (2) a boratingagent.

In said process of making the compound of formula VII, or the enantiomerof said compound, preferred substituents for R¹ and R² are as statedabove for said process of making the compound of formula X. In anotherpreferred embodiment, X is bromo or iodo, and said compound of formulaVI is treated with (1) methyl lithium, (2) butyl lithium, and (3) saidborating agent which is selected from borane-tetrahydrofuran complex,triisopropyl borate, and trimethyl borate. Most preferably, the compoundof formula VI is (3S,4R)-3-benzyl-7-bromo-chroman-4-ol and said boratingagent is borane-tetrahydrofuran complex.

In a further aspect of the invention, the compound of formula VI, or theenantiomer of said compound, wherein R¹, R² and X are as defined above,is prepared by treating a compound of the formula

or the enantiomer of said compound of formula V in the preparation ofthe enantiomer of the compound of formula VI, wherein R¹, R² and X areas defined above and X is attached at position 4 or 5 of the phenylring, and Y is halo or nitro, with a base, optionally in the presence ofadded copper salts.

In said process of making the compound of formula VI, or the enantiomerof said compound, preferred substituents for R¹, R² and X are as statedabove for said process of making the compound of formula VII. In anotherpreferred embodiment, Y is halo, and said base is potassiumtert-butoxide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, cesium carbonate, or sodium hydride. Mostpreferably, said base is potassium tert-butoxide and the compound offormula V is(1S,2R)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.

In a further aspect of the invention, the compound of formula V, or theenantiomer of said compound, wherein R¹, R², X and Y are as definedabove, is prepared by treating a compound of the formula

or the enantiomer of said compound of formula IV in the preparation ofthe enantiomer of the compound of formula V, wherein R¹, R², X and Y areas defined above and X is attached at position 4 or 5 of the phenylring, and X_(c) is a chiral auxiliary, with a hydride reducing agent.

In said process of making the compound of formula V, or the enantiomerof said compound, preferred substituents for R¹, R², X and Y are asstated above for said process of making the compound of formula VI. Inanother preferred embodiment, X_(c) is (R)-4-benzyl-2-oxazolidinone,(S)-4-benzyl-2-oxazolidinone,(3S,4R)-4-methyl-5-phenyl-oxazolidin-2-one, or(3S,4R)-4-methyl-5-phenyl-oxazolidin-2-one, wherein said X_(c) isattached at the nitrogen of the oxazolidin-2-one ring, and said reducingagent is lithium borohydride, lithium aluminum hydride, sodiumborohydride, or calcium borohydride. Most preferably, the compound offormula IV is[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate or[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,and said reducing agent is lithium borohydride.

In a further aspect of the invention, the compound of formula IV, or theenantiomer of said compound, wherein R¹, R², X, X_(c) and Y are asdefined above, is prepared by treating a compound of the formulaR¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are as defined above, with (1) aLewis acid, (2) a base, and (3) a compound of formula

wherein R², X and Y are as defined above and X is attached at position 4or 5 of the phenyl ring.

In said process of making the compound of formula IV, or the enantiomerof said compound, preferred substituents for R¹, R², X, X_(c) and Y areas stated above for said process of making the compound of formula V. Inanother preferred embodiment, said Lewis acid is a boron halide orsulfonate, and said base is triethylamine or diisopropylethylamine. Mostpreferably, said compound of formula R¹—CH₂C(O)—X_(c) is(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one, said compound offormula III is 4-bromo-2-fluoro-benzaldehyde, said Lewis acid isdibutylboron triflate, and said base is triethylamine.

In a further aspect of the invention, the compound of formula IV, or theenantiomer of said compound, wherein R¹, R², X, X_(c) and Y are asdefined above, is prepared by treating a compound of the formulaR¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are as defined above, with (1) atitanium(IV) halide, (2) a base optionally followed by treatment with adonor ligand, and (3) a compound of formula

wherein R², X and Y are as defined above and X is attached at position 4or 5 of the phenyl ring.

In said process of making the compound of formula IV, or the enantiomerof said compound, preferred substituents for R¹, R², X, X_(c) and Y areas stated above for said process of making the compound of formula V. Inanother preferred embodiment, said titanium(IV) halide is titaniumtetrachloride, and said base is a tertiary amine or tertiary diaminebase. In another preferred embodiment, said base is triethylamine orN,N,N′,N′-tetramethylethylenediamine,and said treatment with said baseis followed by treatment with a donor ligand selected from1-methyl-2-pyrrolidinone, dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate,and 2,2′-dipyridyl. Most preferably, said compound of formulaR¹—CH₂C(O)—X_(c) is(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one,said compound offormula III is 4-bromo-2-fluoro-benzaldehyde, said base isN,N,N′,N′-tetramethylethylenediamine, and said donor ligand is1-methyl-2-pyrrolidinone.

In a further aspect of the invention, said compound of formula IX, orthe enantiomer of said compound, wherein R¹, R², R³ and R⁴ are asdefined above, is prepared by coupling a compound of the formula

or the enantiomer of said compound in the preparation of the enantiomerof the compound of formula IX, wherein R¹ and R² are as defined aboveand X′, which is attached at position 6 or 7 of the chroman ring, ishalo or C₁-C₄ perfluoroalkylsulfonate, with a compound of the formula

wherein R³ and R⁴ are as defined above, in the presence of a base orfluoride salt and a palladium catalyst.

In the process of preparing the compound of formula IX, or theenantiomer of said compound, as recited directly above, preferredsubstituents for R¹, R², R³ and R⁴ are as stated above for the processof making the compound of formula X. In another preferred embodiment, X′is preferably bromo, iodo, or trifluoromethanesulfonate, the palladiumcatalyst is preferably selected fromtetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),and 10% palladium on carbon, and the base or fluoride salt is selectedfrom sodium carbonate, triethylamine, sodium bicarbonate, cesiumcarbonate, tripotassium phosphate, potassium fluoride, cesium fluoride,sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride.Most preferably, the compound of formula VI is(3S,4R)-3-benzyl-7-bromo-chroman-4-ol, the compound of formula XIV is2-(2,2-dimethyl-propoxycarbonyl-5-trifluoromethyl-benzeneboronic acid,the base or fluoride salt is sodium carbonate, and the palladiumcatalyst is tetrakis(triphenylphosphine)palladium(0).

In a further aspect of the invention, the compound of formula XIV,wherein R³ and R⁴ are as defined above, is prepared by hydrolyzing acompound of the formula

wherein R³ and R⁴ are as define above, the dashed line indicates a bondor no bond between the B and N atoms, n and m are independently 2 to 5,and R⁸ is H or C₁-C₆ alkyl. R⁸ is preferably H and preferredsubstituents for R³ and R⁴ are as stated above for said process ofmaking a compound of formula X. Preferably, said hydrolysis is effectedwith an acid, such as hydrochloric acid, and n and m are each 2. Mostpreferably, said compound of formula XVI is2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester.

In a further aspect of the invention, the compound of formula XVI,wherein R³, R⁴ and R⁸ are as defined above, is prepared by reacting acompound of formula XIV, wherein R³ and R⁴ are as defined above, with acompound of formula HO(CH₂)_(m)—N(R⁸)—(CH₂)_(n)OH (formula XV), whereinn, m and R⁸ are as defined above. In said process of preparing thecompound of formula XVI, preferred substituents for R³ and R⁴ are asstated above for said process of preparing a compound of formula X. Mostpreferably, said compound of formula XIV is2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acidand said compound of formula XV is diethanolamine.

In a further aspect of the invention, the compound of formula XIV,wherein R⁴ and R³ are as defined above, is prepared by hydrolyzing acompound of the formula

wherein R³ and R⁴ are as defined above and R⁷ is C₁-C₆ alkyl. Saidhydrolysis is preferably effected with an acid, such as hydrochloricacid. Preferred substituents for R³ and R⁴ are as stated above for saidprocess of making a compound of formula X.

In a further aspect of the invention, the compound of formula XVI,wherein R³, R⁴ and R⁷ are as defined above, is prepared by treating acompound of the formula

wherein R³ and R⁴ are as defined above, with a metal amide base in thepresence of a tri-(C₁-C₆ alkyl)borate.

In said process of making the compound of formula XIII, preferredsubstituents for R³ and R⁴ are as stated above for said process ofmaking the compound of formula X. In another preferred embodiment, saidmetal amide base is selected from lithium diisopropylamide, lithiumdiethylamide, lithium 2,2,6,6-tetramethylpiperidine, andbis(2,2,6,6-tetramethylpiperidino)magnesium, and saidtri-(C₁-C₄alkyl)borate is selected from triisopropylborate,triethylborate, and trimethylborate. Most preferably, the compound offormula XII is 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester,said metal amide base is lithium diisopropylamide, and said tri-(C₁-C₆alkyl)borate is triisopropylborate.

In a further aspect of the invention, the compound of formula X, or theenantiomer of said compound, wherein R¹, R², and R³ are as definedabove, is reacted with a secondary amine of the formula NHR⁵R⁶, whereinR⁵ and R⁶ are as defined above, to form an ammonium carboxylate of theformula

or the enantiomer of said compound of formula XVII, wherein R¹, R², R³,R⁵ and R⁶ are as defined above. Preferred substituents for R¹, R², andR³ are as stated above for said process of making a compound of formulaX. In said secondary amine, R⁵ and R⁶ are each preferably cyclohexyl.Most preferably, said compound of formula XVII is (3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethylbenzoate.

The invention also relates to a process of preparing a compound of theformula

or the enantiomer of said compound, wherein R¹ and X_(c) are as definedabove for said process of preparing a compound of formula V, and R¹¹ isC₁-C₉ alkyl, C₂-C₉ alkenyl or phenyl substituted by Y in the 2 position,X in the 4 or 5 position, and R² in one of the remaining positions ofthe phenyl moiety, wherein Y, X and R² are as defined above for saidprocess of preparing a compound of formula V, by treating a compound ofthe formula R¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are as defined above,with (1) a titanium(IV) halide, (2) a base optionally followed bytreatment with a donor ligand, and (3) less than 2 equivalents,preferably about 1 equivalent, of a compound of the formula R¹¹—C(O)H,wherein R¹¹ is as defined above, relative to the amount of said compoundof formula R¹—CH₂C(O)—X_(c). Preferred substituents and reagents forsaid process of preparing said compound of formula XIX, or theenantiomer of said compound, are as stated above for said process ofpreparing a compound of formula IV using said titanium(IV) halide.

The invention also relates to a compound of the formula

and to the enantiomer of said compound, wherein R¹, R², X and Y are asstated above for said process of preparing a compound of the formula VI.

In said compound of formula V, and the enantiomer of said compound,preferred substituents for R¹, R², X and Y are as stated above for saidprocess of preparing a compound of the formula VI. Most preferably, saidcompound of formula V is(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.

The invention also relates to a compound of the formula

and to the enantiomer of said compound, wherein R¹ and R² are as statedabove for said compound of formula V and X′ is halo or C₁-C₄perfluoroalkylsulfonate and is attached at position 6 or 7 of thechroman ring.

In said compound of formula VI, and the enantiomer of said compound,preferred substituents for R¹ and R² are as stated above for saidcompound of formula V, and X′ is preferably bromo, iodo, ortrifluoromethanesulfonate. Most preferably, said compound of the formulaVI is (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

The invention also relates to a compound of the formula

and to the enantiomer of said compound, wherein R¹ and R² are as statedabove for said compound of formula VI.

In said compound of formula VII, and the enantiomer of said compound,preferred substituents for R¹ and R² are as stated above for saidcompound of formula VI. Most preferably, said compound of the formulaVII is (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid.

The invention also relates to a compound of the formula

and to the enantiomer of said compound, wherein R¹, R², R³ and R⁴ are asstated above for said process of preparing a compound of the formula Xand the benzoate moiety is attached to position 6 or 7 of the chromanring.

In said compound of formula IX, and the enantiomer of said compound,preferred substituents for R¹, R², R³ and R⁴ are as stated above forsaid process of preparing a compound of the formula X. Most preferably,the compound of formula IX is(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoacideethylester.

The invention also relates to a compound of the formula

wherein R³, R⁴ and R⁷ are as stated above for said process of preparinga compound of the formula XIV using a compound of formula XIII.

In said compound of formula XII, preferred substituents for R⁷, R³ andR⁴ are as stated above for said process of preparing a compound of theformula XIV using a compound of formula XIII.

The invention also relates to a compound of the formula

wherein R³ and R⁴ are as stated above for said compound of formula XIII.

In said compound of formula XIV, preferred substituents for R³ and R⁴are as stated above for said compound of formula XII. Most preferably,said compound of the formula XIV is2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid.

The invention also relates to compounds of the formula

wherein the dashed line indicates a bond or no bond between the B and Natoms, n and m are independently 2 to 5, R³ and R⁴ are as defined abovefor said compound of formula XIV, and R⁸ is H or C₁-C₆ alkyl.

In said compound of formula XVI, n and m are each preferably 2,preferred substituents for R³ and R⁴ are as defined above for saidcompound of formula XIV, and R⁸ is preferably H. Most preferably, thecompound of formula XVI is2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoicacid2,2-dimethyl-propyl ester.

The invention also relates to an ammonium carboxylate compound of theformula

and to the enantiomer of said compound, wherein R¹, R², R³, R⁵ and R⁶are as defined above for said process of preparing a compound of theformula X. Preferred substituents for R¹, R², and R³ are as stated abovefor said process of making a compound of formula X. In the ammoniummoiety, R⁵ and R⁶ are each preferably cyclohexyl. Most preferably, saidcompound of formula XVII is(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethylbenzoate.

The present invention also relates to a compound of the formula

and to the enantiomer of said compound, wherein R¹, R², X, Y and X_(c)are as defined above for said process of preparing a compound of formulaV. The present invention also relates to solvates of said compound offormula IV and the enantiomer of said compound of formula IV. Preferredsolvates of said compound of formula IV, and the enantiomer of saidcompound, are those formed with a donor ligand selected from1-methyl-2-pyrrolidinone, dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate,and 2,2′-dipyridyl. The preferred compound of formula IV is[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,and the preferred solvate of said compound is[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate.

The term “halo”, as used herein, unless otherwise indicated, meansfluoro, chloro, bromo or iodo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term “alkoxy”, as used herein, includes O-alkyl groups wherein“alkyl” is defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived form an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “heteroaryl”, as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic heterocycliccompound by removal of one hydrogen, such as pyridyl, furyl, thienyl,isoquinolyl, pyrimidinyl, and pyrazinyl.

The term “enantiomer” as used herein in reference to the compound offormula X

means a compound of the formula

The term “enantiomer” as used herein in reference to the compound offormula IX

means a compound of the formula

The term “enantiomer” as used herein in reference to a compound offormula VII

means a compound of the formula

The term “enantiomer” as used herein in reference to a compound of theformula VI

means a compound of the formula

The term “enantiomer” as used herein in reference to a compound of theformula V

means a compound of the formula

The term “enantiomer” as used herein in reference to a compound of theformula IV

means a compound of the formula

The term “enantiomer” as used herein in reference to a compound of theformula XVII

means a compound of the formula

The term “enantiomer” as used herein in reference to a compound of theformula XIX

means a compound of the formula

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention and the preparation of thecompounds of the present invention are illustrated in the followingSchemes. In the following Schemes and discussion that follows, unlessotherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, Y, Z, X,X_(c), and X′ are as defined above. The following Schemes and thediscussion that follows describe the preparation of the compounds offormulas I-XIX. The following Schemes and description that follows alsoapplies to the enantiomers of the compounds of formulas I-XIX, whereinthe term “enantiomer” is as defined above.

Overall, the synthetic sequence in Scheme I involves attaching chiralauxiliary X_(c) to R¹-containing compound I (step 1), asymmetric aldolcondensation with aldehyde III (step 2 or 2′), reductive removal of thechiral auxiliary from aldol IV (step 3), base-mediated cyclization ofdiol V (step 4), lithiation and boration of halochromanol VI (step 5),coupling boronic acid VII with aryl halide or sulfonate VIII (step 6),and hydrolysis of ester IX (step 7).

In step 1 of Scheme 1, chiral auxiliary HX_(c) is converted to thecorresponding anion by treatment with a suitably strong base, such as analkyllithium base, preferably butyllithium, in an aprotic solvent, suchas an ethereal solvent, preferably tetrahydrofuran (THF), at atemperature of approximately −80 to 0° C., preferably −78 to −55° C.,over a period of about 20 minutes to one hour. Substituent X_(c) is achiral auxiliary that is suitable to control relative and absolutestereochemistry in asymmetric aldol reactions. Examples of HX_(c)include (R)-4-benzyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone,(4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one, and(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one. The resulting anion istreated with acylating agent I, wherein group W is a halide, preferablychloride, and R¹ is as defined above, in the same solvent at atemperature of approximately −80 to 0° C., preferably about −75° C.,over a period of about one hour, and then warmed to approximately −20 to20° C., preferably about 0° C., before aqueous workup, which ispreferably done by treatment with aqueous sodium bicarbonate, to yieldacylated chiral auxiliary II.

Step 2 of Scheme 1 is an “Evans aldol” reaction that is performed underconditions that are analogous to those described in Evans, D. A.;Bartroli, J.; Shih, T. L., J. Am. Chem. Soc. 1981, 103, 2127 and Gage,J. R.; Evans, D. A., Org. Syn. 1989, 68, 83, both of which referencesare incorporated herein by reference. In particular, in step 2 of Scheme1, the acylated chiral auxiliary II is treated with a Lewis acid, abase, and substituted benzaldehyde III to yield alcohol IV with a highdegree of stereoselectivity. Benzaldehyde III is substituted with orthosubstituent Y which serves as a leaving group during cyclization step 4,group X (or X′ for Scheme 2, in particular coupling step 4 of Scheme 2)which is substituted by the aryl sidechain during coupling step 6, andsubstituent R² which is as defined above. Substituent X (or X′ forScheme 2) is attached at position 4 or 5 of the phenyl moiety ofbenzaldehyde III. The leaving group Y is typically a halo or nitro groupand X is a halide (and, for Scheme 2, X′ is a halide or C₁-C₄perfluoroalkylsulfonate). To prepare aldol product IV, acylated chiralauxiliary II is treated with a boron halide or sulfonate, such as adialkylboron sulfonate, preferably dibutylboron triflate, in an aproticsolvent, such as dichloromethane, 1,2-dichloroethane, toluene, ordiethyl ether, preferably dichloromethane, at a temperature of about −78to 40° C., preferably −5° C., over a period of about 20 minutes,followed by treatment with a tertiary amine base, such as triethylamineor diisopropylethylamine, preferably triethylamine, at a temperature ofabout −78 to 40° C., preferably −5 to 5° C., over a period of about onehour. This mixture is treated with substituted benzaldehyde III at atemperature of about −100 to 0° C., preferably about −70° C., over aperiod of about 30 minutes. This mixture is allowed to warm to atemperature of about −20 to 25° C., preferably about −10° C., over aperiod of about one hour, and then treated with a protic oxidativequench, preferably by the successive addition of a pH 7 buffer solution,methanol, and aqueous hydrogen peroxide, at a temperature of less thanabout 15° C., to yield alcohol IV.

Step 2′ of Scheme 1 is an alternative, and preferable, method ofproviding alcohol IV using a titanium-containing Lewis acid. In step 2′of Scheme 1, acylated chiral auxiliary II is treated with a titanium(IV)halide, preferably titanium tetrachloride, in an aprotic solvent such asdichloromethane, 1,2-dichloroethane, or toluene, preferablydichloromethane, at a temperature of about −80 to 0° C., preferably −80to −70° C., over a period of about 30 minutes with additional stirringfor about 30 minutes, followed by treatment with a tertiary amine ortertiary diamine base, such as triethylamine orN,N,N′,N′-tetramethylethylenediamine, preferablyN,N,N′,N′-tetramethylethylenediamine, at a temperature of about −80 to0° C., preferably −80 to −65° C., over a period of about 30 minutes.This is optionally, and preferably, followed by treatment with a donorligand, such as 1-methyl-2-pyrrolidinone, dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate,or 2,2′-dipyridyl, preferably 1-methyl-2-pyrrolidinone, at a temperatureof about −80 to 0° C., preferably −80 to −65° C., followed by stirringfor a period of about 30 minutes. This mixture is treated withsubstituted benzaldehyde III at a temperature of about −100 to 0° C.,preferably −80 to −65° C., over a period of about 30 minutes, andallowed to warm to a temperature of −30 to 30° C., preferably 0 to 25°C., over a period of about one to 24 hours, preferably about 4 hours.This mixture is treated with a protic quench, preferably aqueousammonium chloride, at a temperature of −30 to 30° C., preferably 0 to25° C., to yield alcohol IV. Where treatment with a donor ligand isdone, the alcohol IV is, in some cases, provided as a crystallinesolvate with the donor ligand. Stirring the quenched reaction mixturewith a solid support such as Celite® for a period of about 12 hours at atemperature of about 20° C. improves the filtration of the reactionmixture for removal of titanium byproducts.

The titanium aldol conditions of step 2′ of Scheme 1 are preferable andoperationally more simple than the boron aldol conditions of step 2 ofScheme 1 in that they avoid the pyrophoric reagent tributylborane, thecorrosive reagent triflic acid, and their exothermic combination in thepreparation of the Lewis acid dibutylboron triflate. Further, incontrast to titanium aldol reactions described in the literature, suchas in Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F., J. Am.Chem. Soc. 1991, 113, 1047, the titanium aldol conditions of step 2′ ofScheme 1 provide high selectivity with less than two equivalents of thealdehyde III. Preferably, about one equivalent of aldehyde III is usedin this step. The phrase “about one equivalent” as used herein inreference to aldehyde III or a compound of the formula R¹¹C(O)H (asrecited in the claims) means less than 1.5 equivalents of said compound.In the foregoing article by Evans et al., it is reported that twoequivalents of aldehyde would be required for a titanium aldol reactionanalogous to step 2′ of Scheme 1.

In addition to having utility in the preparation of the therapeuticagents of formula X, the titanium aldol conditions of step 2′ of Scheme1 are useful in the preparation of HIV protease inhibitor compounds thatare described in United Kingdom patent application number 2,270,914(published Mar. 30, 1994) and in B. D. Dorsey et al., TetrahedronLetters, 1993, 34(12), 1851. Scheme 4 illustrates the application oftitanium aldol reaction to aldehyde XVIII in which R¹¹ is C₁-C₉ alkyl,C₂-C₉ alkenyl, or phenyl substituted by Y in the 2 position, X in the 4or 5 position, and R² in one of the remaining positions of the phenylmoiety, wherein Y, X and R² are as defined above. The reactionconditions for Scheme 4 are the same as those described above for step2′ of Scheme 1. Aldehyde XVIII encompasses aldehyde III from Scheme 1,and alcohol XIX encompasses alcohol IV from Scheme 1. The reaction ofScheme 4 can be used to prepare the HIV protease inhibitor compoundsthat are described in United Kingdom patent application number2,270,914, referred to above, where R¹¹ is C₁-C₉ alkyl or C₂-C₉ alkenyl,preferably 3-cyclohexylpropenyl.

Table 1 below illustrates how the product of Scheme 4 or step 2′ ofScheme 1 can vary depending on the reaction conditions that are used,and, in particular, how the diastereoselectivity increases by increasingthe amount TMEDA from 1.2 to 3 equivalents and by the addition of 2equivalents of NMP. In Table 1, 1.0 equivalent of aldehyde RCHO was usedfor each reaction, x and y represent equivalents of base and NMP,respectively, NMP means 1-methyl-2-pyrrolidinone, TMEDA meansN,N,N′,N′-tetramethylethylenediamine, NEtiPr₂ meansdiisopropylethylamine, and the ratio of diastereomers was determined byHPLC. The aldol isomers were identified by separation and conversion toknown carboxylic acid isomers by hydrolysis with LiOH/H₂O₂ according toprocedures analogous to those described in Van Draanen, N. A.;Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H., J. Org. Chem. 1991,56, 2499 and Gage, J. R.; Evans, D. A., Org. Svn. 1989, 68, 83. Thedesired isomer is indicated in bold.

TABLE 1 enolization ratio of aldol RCHO x base y NMP temperaturediastereomers

1.2 NetiPr₂ 0 NMP  0° C. 33:—:2:65 (syn:anti:syn:anti) ″ 1.2 TMEDA 0 NMP 0° C. 22:—:55:23 ″ 1.2 NEtiPr₂ 0 NMP −78° C. 29:—:10:62 ″ 1.2 TMEDA 0NMP −78° C. 16:—57:28 ″ 2 TMEDA 0 NMP −78° C. 2:—86:11 ″ 3 TMEDA 0 NMP−78° C. 2:—94:5 ″ 3 TMEDA 2 NMP −78° C. 1:—:99:—

1.2 TMEDA 0 NMP −78° C. —:—:11:89 (anti:anti:syn:syn) ″ 3 TMEDA 2 NMP−78° C. —:—:—:100

1.2 TMEDA 0 NMP −78° C. 28:39:33:— ″ 3 TMEDA 2 NMP −78° C. 4:92:3:2

1.2 TMEDA 0 NMP −78° C. 18:40:42:— ″ 3 TMEDA 2 NMP −78° C. 2:96:2:—

In step 3 of Scheme 1, chiral auxiliary X_(c) is removed (and optionallyrecovered for reuse in step 1), and the oxidation state of compound IV(acid level) is reduced to the desired alcohol V according to aprocedure analogous to the procedure described in Penning, T. D.;Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B.W.; Yu, S. S., Syn. Commun. 1990, 20, 307, which is incorporated hereinby reference. In this process, alcohol IV is treated with a hydridereducing agent, such as lithium borohydride, lithium aluminum hydride,sodium borohydride, or calcium borohydride, preferably lithiumborohydride, in an ethereal solvent such as THF, diisopropyl ether, ormethyl tert-butyl ether, preferably THF, typically containing a proticsolvent, such as water, ethanol, or isopropanol, at a temperature ofabout −78° C. to reflux temperature, preferably 0° C. to ambienttemperature (20-25° C.). After a period of one to 24 hours, typically 12hours, the reaction is quenched with water with the optional subsequentaddition of hydrogen peroxide. Chiral auxiliary HX_(c) can be recoveredfor reuse in step 1 by selective precipitation, or by extraction ofHX_(c) into aqueous acid, preferably hydrochloric acid, from a solutionof diol V in an organic solvent such as diisopropyl ethyl or a mixtureof ethyl acetate and hexane, followed by neutralization of the aqueousacidic extracts with base, and extraction of HX_(c) into an organicsolvent.

Step 4 of Scheme 1 is an intramolecular aromatic substitution wherebythe primary hydroxyl in diol V displaces ortho leaving group Y togenerate the chromanol ring system of VI. In particular, diol V, inwhich leaving group Y is a halo or nitro group, preferably a fluorogroup, is treated with a base, such as potassium tert-butoxide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, cesiumcarbonate, or sodium hydride, preferably potassium tert-butoxide, in anaprotic solvent such as THF, dimethyl sulfoxide, or1-methyl-2-pyrrolidinone, preferably THF, optionally in the presence ofadded copper salts, at a temperature of between ambient temperature and130° C., preferably about 70° C., for a period of one to 24 hours,typically about four hours, giving chromanol VI. In chromanol VI, thesubstituent X (or X′ for Scheme 2) is attached at position 6 or 7 of thechroman ring.

In step 5 of Scheme 1, substituent X in chromanol VI is converted tolithium and then a boronic acid group. For lithiation, chromanol VI ispreferably treated first with methyl lithium to form the lithiumalkoxide followed by butyl lithium to form the aryl lithium. In thisprocess, chromanol VI, in which X is a halide, preferably bromide oriodide, is treated with two equivalents of alkyllithium, preferablyfirst with one equivalent of methyllithium followed by one equivalent ofbutyl lithium, in an ethereal solvent, preferably THF, at a temperatureof −78 to 0° C., preferably −70 to −65° C., for a period of about onehour, followed by treatment with a borating agent, such asborane-tetrahydrofuran complex, triisopropyl borate, or trimethylborate, preferably borane-THF complex, at a temperature of −78 to 0° C.,preferably −70 to −65° C., over a period of about 30 minutes, followedby quenching with water or optionally aqueous acid at a temperature ofabout −65° C. to ambient temperature, preferably at about 0° C., givingboronic acid VII in which the boronic acid moiety is attached atposition 6 or 7 of the chroman ring.

Step 6 of Scheme 1 is a Suzuki coupling between boronic acid VII andcompound VIII to form the biaryl bond of compound IX. In compound VIII,Z is a halide or sulfonate, preferably bromide, iodide, ortrifluoromethanesulfonate, R⁴ is C₁-C₆ alkyl and R³ is as defined above.This procedure is analogous to the procedure described in Miyaura, N.;Suzuki, A., Chem. Rev. 1995, 95, 2457, which is incorporated herein byreference. This procedure is preferable to the coupling of zinc or tinspecies due to the difficulty of preparing organozincs on a large scaleand the toxicity of organotin compounds. In this process, a mixture ofboronic acid VII, arene VIII, a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),or 10% palladium on carbon, preferably 10% palladium on carbon, and abase or fluoride salt, such as sodium carbonate, triethylamine, sodiumbicarbonate, cesium carbonate, tripotassium phosphate, potassiumfluoride, cesium fluoride, or tetrabutylammonium fluoride, preferablypotassium fluoride, in a solvent such as ethanol, dimethoxyethane, ortoluene, optionally containing water, preferably ethanol, are stirred ata temperature of between ambient temperature and 130° C., preferablyreflux temperature, for a period of about one to about 24 hours,preferably about three hours, giving biaryl IX in which the benzyl estermoiety is attached at position 6 or 7 of the chroman ring.

In step 7 of Scheme 1, ester IX is treated with aqueous hydroxide base,such as aqueous sodium hydroxide, in an alcoholic solvent, such asisopropyl alcohol, at a temperature of between 40° C. and refluxtemperature, preferably reflux temperature, for a period of about one toabout 24 hours, preferably about six hours. The reaction mixture iscooled to ambient temperature and partitioned between aqueous base andan organic solvent, such as a mixture of hexane and isopropyl ether. Theaqueous solution is acidified, and the final compound X is extractedinto an organic solvent such as ethyl acetate. This method of extractingthe compound X with organic solvents removes neutral impurities which isparticularly advantageous in the last step of this synthesis.

To facilitate the handling of carboxylic acid X, this compound can betreated with a secondary amine of the formula NHR⁵R⁶, wherein R⁵ and R⁶are as defined above, in a solvent such as toluene, to form an ammoniumcarboxylate of the formula

wherein R¹, R², R³, R⁵ and R⁶ are as defined above. Ammonium carboxylateXVII can be treated with an aqueous acid such a hydrochloric acid orsulphuric acid, preferably hydrochloric acid, in a solvent such as ethylacetate, toluene, or methylene chloride, preferably ethyl acetate, at atemperature ranging from 0° C. to ambient temperature for a period of 30minutes to 3 hours, preferably 1 hour, to provide carboxylic acid X.

Scheme 2 illustrates an alternative to the coupling sequence of steps 5and 6 of Scheme 1. The process of Scheme 2 is preferred. Step 1 ofScheme 2 is an esterification of carboxylic acid XI with alcohol R⁴OH,in which R³ and R⁴ are as defined above, to generate ester XII. In thisprocess, carboxylic acid XI is treated with alcohol R⁴OH, preferably aprimary or secondary alcohol such as 2,2-dimethyl-propyl alcohol, and anacid such as sulfuric acid, hydrochloric acid, methanesulfonic acid,toluenesulfonic acid, or camphor sulfonic acid, preferably sulfuricacid, in a solvent such as toluene, dichloromethane, or dichloroethane,preferably toluene, at a temperature of 0° C. to reflux temperature,preferably reflux temperature, for a period of one to 24 hours,typically 4 hours, to provide ester XII.

In step 2 of Scheme 2, ester XII is treated with a base and theresulting ortho metallated species is trapped with a trialkylborate togive boronate ester XIII. In step 3 of Scheme 2, the boronate ester XIIIis hydrolyzed to the corresponding boronic acid XIV which is performedby methods known to those skilled in the art. In steps 2 and 3 of Scheme2, ester XII is treated with a metal amide base such as lithiumdiisopropylamide, lithium diethylamide, lithium2,2,6,6-tetramethylpiperidine, orbis(2,2,6,6-tetramethylpiperidino)magnesium, preferably lithiumdiisopropylamide, in the presence of a tri-(C₁-C₄ alkyl)borate, such astriisopropylborate, triethylborate, or trimethylborate, preferablytriisopropylborate, in an ethereal solvent, such as THF, diisopropylether, dioxane, or methyl tert-butyl ether, preferably THF, over atemperature range of about −78° C. to ambient temperature (20-25° C.),preferably about 0° C. After a period of 10 minutes to 5 hours,typically 1 hour, the reaction is quenched with aqueous acid to provideboronic acid XIV.

To facilite the handling of boronic acid XIV before proceeding to step 4of Scheme 2, the boronic acid XIV can be reacted with an aminodiol asillustrated in Scheme 3. In Scheme 3, boronic acid XIV is reacted withaminodiol XV, wherein R⁸, m and n are as defined above, in a solventsuch as isopropanol, ethanol, methanol, hexanes, toluene, or acombination of the foregoing solvents, preferably isopropanol, at atemperature within the range of 0° C. to reflux temperature, preferablyambient temperature, for a period of 15 minutes to 10 hours, preferably10 hours, to provide the amine complex XVI. To proceed with step 4 ofScheme 2, amine complex XV is hydrolyzed to boronic acid XIV accordingto methods known to those skilled in the art. Such methods include theuse of aqueous acid, such as hydrochloric acid.

Step 4 of Scheme 2 is a Suzuki coupling between boronic acid XIV andchromanol VI to form the biaryl bound of IX. In this process, a mixtureis prepared containing boronic acid XIV, chromanol VI, a palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpailadium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),or 10% palladium on carbon, preferablytetrakis(triphenylphosphine)palladium(0), a base or fluoride salt, suchas sodium carbonate, triethylamine, sodium bicarbonate, cesiumcarbonate, tripotassium phosphate, pottasium fluoride, cesium fluoride,sodium hydroxide, barium hydroxide, or tetrabutylammonium fluoride,preferably sodium carbonate, and a solvent such as toluene, ethanol,dimethoxyethane, optionally containing water, preferably toluenecontaining water. In chromanol VI, which is prepared according to Scheme1, X′, which is attached at position 6 or 7 of the chroman ring,represents a halide or C₁-C₄ perfluoroalkylsulfonate, preferablybromide, iodide, or trifluoromethanesulfonate. The mixture is stirred ata temperature of between ambient temperature and reflux temperature,preferably reflux temperature, for a period of about 10 minutes to about6 hours, preferably 1 hour, to provide biaryl IX.

In step 5 of Scheme 2, ester IX is hydrolyzed to provide the carboxylicacid X as described above for step 7 of Scheme 1.

The present invention is illustrated by the following examples, but itis not limited to the details thereof. In the following examples, theterm “ambient temperature” means a temperature within the range of about20° C. to about 25° C.

EXAMPLE 1 (R)-4-Benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one

To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and500 mg of 2,2′-dipyridyl as an indicator in tetrahydrofuran (9 L) at−78° C. was added over 30 minutes a 2.5 M solution of BuLi in hexanes(2.03 L, 5.14 mol). The temperature of the reaction mixture wasmaintained at less than −55° C. during the addition. The reactionmixture was cooled to −75° C. and hydrocinnamoyl chloride (950 g, 5.63mol) was added over 5 minutes. The reaction mixture was allowed to warmto 0° C., at which point the reaction mixture was judged to be completeby thin layer chromatography (hexanes/ethyl acetate, 2:1). The reactionwas quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water(3.6 L). The aqueous phase was separated and extracted with ethylacetate (3 L). The combined organic layers were washed with 5% aqueoussodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L),dried over magnesium sulfate, and concentrated in vacuo to approximately2 L of a viscous yellow suspension. This slurry was dissolved in ethylacetate (3 L), concentrated to a solid, and dissolved in ethyl acetateat 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooledto 10° C. resulting in the precipitation of solids which were stirred at10° C. for 30 minutes. The solids were collected by filtration, washedwith hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%)of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellowneedles: ¹H NMR (300 MHz, CDCl₃) δ7.14-7.33 (m, 10H), 4.66 (m, 1H), 4.17(t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5,13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746,699 cm⁻¹; mp 102-104° C.

EXAMPLE 2[4R-[3(2R,3R)]]-4-Benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one

To a solution of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one(1064 g, 3.44 mol) in dichloromethane (5.6 L) at −5° C. was addeddibutylboron triflate (1133 g, 4.13 mol) over 20 minutes, followed bythe addition of triethylamine (719 mL, 5.16 mol) while maintaining areaction temperature of less than 5° C. This mixture was cooled to −70°C., and a solution of 4-bromo-2-fluoro-benzaldehyde (699 g, 3.44 mol) indichloromethane (2 L) was added over 30 minutes. The mixture was allowedto warm to −10° C. over 1 hour, at which point it was judged to becomplete by thin layer chromatography (hexanes/ethyl acetate, 2:1). Thereaction was quenched by adding potassium phosphate monobasic-sodiumhydroxide pH 7 buffer (3.5 L) over 30 minutes followed by methanol (1.8L) and 35% aqueous hydrogen peroxide (1.8 L) over 1.5 hours whilemaintaining a reaction temperature of less than 15° C. The organic layerwas separated, washed with saturated aqueous sodium bicarbonate (6.7 L),and diluted with anhydrous ethanol (4 L) and 25% aqueous sodiumbisulfite. The organic layer was separated, washed with water (4 L),dried over magnesium sulfate, and concentrated in vacuo giving 1818 g(103%-crude weight) of[4R-[3(2R,3R)]]-4-benzyl-3-[2-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-oneas a very viscous amber-colored oil: ¹H NMR (400 MHz, CDCl₃) δ7.46 (t,J=8.0 Hz,1H), 7.16-7.32 (m, 10H), 6.94-6.96 (m, 2H), 5.35 (d, J=4.7 Hz,1H), 4.92-5.29 (m, 1H), 4.45-4.51 (m, 1H), 3.92 (m, 2H), 3.01 -3.14 (m,3H), 2.83 (dd, J=3.1, 13.6 Hz, 1H), 2.05 (dd, J=10.0, 13.5 Hz, 1H); IR3460 (br), 1780, 1696, 1483, 1388, 1350, 1209, 1106, 1068, 877, 760,747, 701, 583, 512, 486 cm⁻¹.

EXAMPLE 3[4R-[3(2R,3R)]]-4-Benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-Methyl-2-pyrrolidinone Solvate

To a solution of(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one(12.0 kg, 38.8 mol)in dichloromethane (180 L) at −70° C. to −80° C. was added titaniumtetrachloride (8.8 kg, 46.6 mol) over 30 minutes giving a thicksuspension which was stirred for an additional 30 minutes at −70° C. to−80° C. N,N,N′,N′-Tetramethylethylenediamine (17.6 L, 116.4 mol) wasadded over 30 minutes giving a more fluid reaction mixture.1-Methyl-2-pyrrolidinone (7.6 kg, 77.6 mol) was added, and the reactionmixture was stirred for 30 minutes, all while maintaining a reactiontemperature of less than −65° C. A solution of4-bromo-2-fluoro-benzaldehyde (7.9 kg, 38.8 mol) in dichloromethane (38L) was added over 30 minutes while maintaining a reaction temperature ofless than or equal to −68° C. The reaction mixture was allowed to warmto 20° C. over 8 hours at which point it was cooled to 10° C. andquenched with a solution of 5.0 kg of ammonium chloride in 11 L of waterinducing a white precipitate and an exotherm to 28° C. Celite® (12 kg)was added and the reaction mixture was stirred for 12 hours at 20° C.The reaction mixture was filtered, concentrated atmospherically to anoil, treated with hexanes (120 L), concentrated to approximately 50 L,slowly cooled to 0° C. and granulated for 24 hours. The crude product,24.3 kg, was isolated by filtration, combined with the crude productsfrom two similar reactions in 110 L of dichloromethane, treated with 320L of hexanes, concentrated atmospherically to a final volume ofapproximately 250 L (distillate temperature 65° C.), seeded withauthentic product, and slowly cooled with granulation over 18 hours at20° C. Filtration yielded 67.4 kg (94%) of[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate as a light tan granular solid: ¹H NMR(400 MHz, CDCl₃) δ7.46 (t, J=8.0 Hz, 1H), 7.15-7.29 (m, 10H), 6.94 (dd,J=1.9, 7.2 Hz, 2H), 5.34 (d, J=4.8 Hz, 1H), 4.91-4.96 (m, 1H), 4.44-4.49(m, 1H), 3.90-3.95 (m, 2H), 3.55 (bs, 1H), 337 (dd, J=7.2, 7.2 Hz, 2H),3.00-3.13 (m, 2H), 2.83 (s, 3H), 2.82 (dd, J=3.3, 13.3 Hz, 1H), 2.36(dd, J=8.2, 8.2 Hz, 2H), 1.97-2.06 (m, 3H); IR 3150 (br), 1776, 1695,1652, 1600, 1221, 1050, 996, 953, 875 cm⁻¹; mp 80-83° C.

EXAMPLE 4 (1R,2S)-2-Benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol

A 2 M solution of lithium borohydride in tetrahydrofuran (1.7 L, 3.4mol) was diluted with tetrahydrofuran (1.7 L) and cautiously treatedwith water (61 mL, 3.4 mol) over 15 minutes. This mixture was stirred atambient temperature until hydrogen evolution ceased (0.5 to 1 hour), andthen added to a solution of[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one(1.75 kg, 3.4 mol) in tetrahydrofuran (8.75 L) at 0° C. over 30 minutes.The resulting milky-white suspension was allowed to warm to ambienttemperature over 12 hours at which point it was judged to be complete bythin layer chromatography (hexanes/ethyl acetate, 2:1). The reactionmixture was cooled to 15° C. and quenched with water (5.25 L) over 15minutes and stirred an additional 10 minutes before adding 35% aqueoushydrogen peroxide (2.6 L) over 20 minutes. The reaction mixture wasstirred for 15 minutes and then diluted with ethyl acetate (5.3 L) andwater (4 L). The organic layer was separated and washed with water (5.3L), 5% aqueous sodium bisulfite (5.25 L), and 50% saturated aqueoussodium chloride (7.5 L). Peroxides were detected in the organic layer,so it was further washed with 5% aqueous sodium bisulfite (5 L) and 50%saturated aqueous sodium chloride (6 L). The organic layer wasconcentrated in vacuo to an oil, diluted with ethyl acetate (4 L) andhexanes (13 L), and washed with 1 N aqueous hydrochloric acid (6 times17 L) to remove the (R)-(+)-4-benzyl-2-oxazolidinone. The organic layerwas washed with saturated aqueous sodium bicarbonate (5.3 L), dilutedwith toluene (2 L), and concentrated in vacuo yielding 1138 g (98%) of(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diolas an oil:¹H NMR (400 MHz, CDCl₃) δ7.47-7.51 (m, 1H), 7.33 (dd, J=1.9, 8.3 Hz,1H), 7.15-7.25 (m, 4H), 7.04-7.06 (m, 2H), 5.39 (d, J=2.6 Hz, 1H), 3.77(dd, J=3.0, 10.7 Hz, 1H), 3.64 (dd, J=5.0, 10.8 Hz, 1H), 3.44 (bs, 1H),2.68 (dd, J=11.0, 13.8 Hz, 1H), 2.59 (dd, J=4.1, 13.9 Hz, 1H),2.15-2.20(m, 1H), 2.01 (bs, 1H); IR 3370 (br), 3269 (br), 1485, 1406,1213,1033,1021,870,700 cm⁻¹.

EXAMPLE 5 (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol

A 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran(6.55 L, 6.55 mol) was added over 20 minutes to a solution of(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975 g,5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. Themixture was slowly heated to 60° C. under aspirator vacuum to displacethe tetrahydrofuran from the reaction mixture, and then heated at 60 to65° C. for 5 hours under aspirator vacuum at which point the reactionwas judged to be complete according to thin layer chromatography(hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambienttemperature and quenched by adding water (10 L) followed by 1 N aqueoushydrochloric acid (10 L). The resulting tan suspension was filtered,washed with water (2 L), and dissolved in ethyl acetate (12 L). Thissolution was washed with water (two times 12 L), concentrated to a lowvolume, dissolved in isopropyl ether (4 L), and concentrated underatmospheric pressure at 50 to 60° C. to 1.0 L, at which point solidsbegan to precipitate. The resulting suspension was cooled to ambienttemperature, stirred for 12 hours, concentrated to one-half its volume,cooled to 0 to 5° C., and filtered giving 916 g (49%) of(3S,4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate wasconcentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L)at reflux, cooled to ambient temperature, stirred, and filtered yieldingan additional 82 g of solid. The filtrate was concentrated andchromatographed on silica gel (60-230 mesh) eluting with 3:1hexanes/ethyl acetate. Product-rich fractions were concentrated andrecrystallized from isopropyl ether yielding an additional 82 g ofsolid. The total yield of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080g (58%): ¹H NMR (400 MHz, CDCl₃) δ7.29-7.33 (m, 2H), 7.21-7.25 (m, 1H),7.15-7.19(m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs, 1H), 4.21 (dd, J=2.6,11.3 Hz, 1H), 3.97 (dd, J=4.5, 11.3 Hz, 1H), 2.68 (dd, J=6.5, 13.8 Hz,1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m, 1H), 1.85 (d, J=4.3Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1573, 1493, 1480, 1410, 1219,1070, 1052, 1023, 859, 700 cm⁻¹; mp 143.5-144.0° C.

EXAMPLE 6 (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol

To a solution of(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (preparedfrom 33.5 kg (54.8 moles) of[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate without isolation) in 185 L oftetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide.The reaction mixture was heated at reflux for 4 hours at which point thereaction was found to be complete by thin layer chromatography(hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambienttemperature, quenched with 170 L of water, diluted with 83 L of ethylacetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L ofconcentrated hydrochloric acid. The organic layer was concentrated undervacuum to approximately 38 L of a slurry, diluted with 76 L of isopropylether, warmed to dissolve the solids, slowly cooled to 0° C., andgranulated at 0° C. for 12 hours. (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol,5.1 kg of white solid, was isolated by filtration. The mother liquor waswashed with 4 L of saturated aqueous sodium chloride, concentrated to afinal volume of 57 L, and granulated at 0° C. for 12 hours affording a4.3 kg second crop of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

A second identical reaction mixture was quenched, diluted with ethylacetate, and acidified as described above. The organic layer was driedover 10 kg of magnesium sulfate, concentrated atmospherically toapproximately 30 L of a slurry, diluted with 38 L of isopropyl ether,concentrated to approximately 57 L, slowly cooled, and granulated at 0to10° C. for 12 hours. (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol, 8.7 kg, wasisolated by filtration. The mother liquor was combined with the motherliquor from the second crop from the first reaction, concentrated to anoil, solidified by cooling, granulated in 6 L of isopropyl ether at 20°C. for 12 hours and 0° C. for 2 hours, and filtered giving 6.3 kg of(3S,4R)-3-benzyl-7-bromo-chroman-4-ol after washing with cold isopropylether. The combined crops from both reactions were dried giving 20.8 kg(59%) of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

EXAMPLE 7 (3S,4R)-(3-Benzyl-4-hydroxy-chroman-7-yl)-boronic Acid

To a solution of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (377 g, 1.18 mol)in tetrahydrofuran (5.6 L) at −75° C. was added a 1.48 M solution ofmethyllithium in ether (1.6 L, 2.37 mol) over 45 minutes whilemaintaining a temperature of less than −65° C. The reaction mixture wasstirred at less than −65° C. for 1 hour, followed by the addition of a2.5 M solution of butyllithium in hexanes (440 mL, 1.3 mol) over 15minutes. The reaction mixture was stirred at less than −65° C. for 1hour, followed by the addition of a 1.0 M solution ofborane-tetrahydrofuran complex in tetrahydrofuran (5.9 L, 5.9 mol) over30 minutes. The reaction mixture was warmed to 0° C., quenched by addingwater (4.4 L), adjusted to pH 2 with 1 N aqueous hydrochloric acid (4L), and extracted with isopropyl ether (4 L). The aqueous layer wasextracted with isopropyl ether (4 L), and the combined organic layerswere washed with 0.5 N aqueous sodium hydroxide (7.2 L). The aqueouslayer was adjusted to pH 3 with 1 N aqueous hydrochloric acid (5.5 L)and extracted with ethyl acetate (5.4 L and 2.7 L). The combined ethylacetate layers were dried over magnesium sulfate, and concentrated invacuo yielding 304.5 g (91%) of(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronicacid as a yellow foam:¹H NMR (300 MHz, CDCl₃) δ7.35-7.00 (m, 8H), 4.42 (d, J=4.1 Hz, 1H), 4.19(d, J=1H), 3.90 (m, 1H), 2.68 (dd, J=6.2, 13.8 Hz, 1H), 2.47 (m, 1H),2.15 (m, 1H); IR 3330 (br), 1413, 1348, 1320, 1211, 1025, 749, 730, 700c⁻¹.

EXAMPLE 8(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid Ethyl Ester

A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g, 2.1 mol),(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid (627 g, 2.2 mol),potassium fluoride (366 g, 6.3 mol), 10% palladium on carbon (157 g, 50%water wet), and anhydrous ethanol (6.27 L) was heated at reflux for 3hours at which point thin layer chromatography (toluene/acetic acid,5:1) indicated the reaction to be complete. The reaction mixture wasdiluted with isopropyl ether (8 L), filtered through Celiteeand washedwith 10% aqueous sodium bicarbonate (1.5 L). The aqueous layer wasseparated and extracted with isopropyl ether (3 L). The combined organiclayers were washed with water (6 L), dried over magnesium sulfate, andtreated with Darco®G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) atambient temperature. This mixture was filtered through a pad of silicagel (70-230 mesh) and concentrated in vacuo to 922 g of dark oil. Thisoil was diluted with ethyl acetate (1 L) and filtered through a columnof silica gel (2 kg) eluting with ethyl acetate giving a light ambersolution which was concentrated to afford 897 g (92%) of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacidethyl ester as a light amber oil: ¹H NMR (400 MHz, CDCl₃) δ7.89 (d,J=8.1 Hz, 1H), 7.63-7.67 (m, 2H), 7.18-7.38 (m, 6H), 6.91 (dd, J=1.8,7.8 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.55 (bs, 1H), 4.25 (dd, J=2.7,11.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (ddd, J=1.0, 4.5,11.2 Hz,1H), 2.75 (dd, J=6.4, 13.9 Hz, 1H), 2.56 (dd, J=9.3, 13.8 Hz, 1H), 2.26(m, 1H), 1.93 (d, J=4.3 Hz, 1H), 1.09 (t, J=7.2 Hz, 3H); IR 3307 (br),3216 (br), 1734, 1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050 cm⁻¹.

EXAMPLE 9(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid

A mixture of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester (897 g, 1.93 mol) and 10% aqueous sodium hydroxide (980mL, 2.72 mol) in isopropyl alcohol (9 L) was heated at reflux for 6hours, cooled to ambient temperature, and stirred for 12 hours. Thereaction mixture was diluted with water (13.5 L), hexanes (9 L), andisopropyl ether (4.5 L). The aqueous layer was separated and extractedwith hexanes (9 L) and isopropyl ether (4.5 L), adjusted to pH 2 with 2N aqueous hydrochloric acid, and extracted with ethyl acetate (8 L and 4L). The combined ethyl acetate extracts were washed with water (6 L),dried over magnesium sulfate, and concentrated in vacuo to a dark amberoil which was diluted with toluene (2 L) and concentrated again to anoil. The oil was dissolved in toluene (4.2 L) at 60° C., and hexanes(8.8 L) were added at a rate to maintain a temperature of greater than50° C. The tan solids which precipitated upon slowly cooling to ambienttemperature over several hours were filtered and washed with 2:1hexane/toluene (2 L). These solids were dissolved in toluene (5 L) at60° C., treated with Darco®G-60, filtered, washed with toluene, andconcentrated in vacuo to approximately 4.0 L. This mixture was heated to50-60° C.,treated drop-wise with hexanes(8.6 L), cooled, and granulatedat 5° C. for 1 to 2 hours. The resulting solids were filtered, washedwith 2:1 hexanes/toluene (2 L), and the wet cake was stirred withhexanes (4 L) at reflux for 30 minutes. This mixture was cooled toambient temperature, granulated for 1 hour, filtered, and the resultingsolids were dried under vacuum overnight to provide 450 g (55%) of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacidas an off white solid: ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=8.1 Hz, 1H),7.66 (dd, J=1.1, 8.1 Hz, 1H), 7.63 (s, 1H), 7.15-7.32 (m, 6H), 6.89 (dd,J=1.7, 7.9 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.1 (bs, 2H), 4.50 (d, J=4.3Hz, 1H), 4.1 8 (dd, J=2.7, 11.2 Hz, 1H), 3.94 (dd, J=4.6, 11.0 Hz, 1H),2.74 (dd, J=6.1, 13.8 Hz, 1H), 2.51 (dd, J=9.4, 13.9 Hz, 1H),2.22(m,1H); IR 3454,3218 (br), 1699, 1431, 1337, 1299, 1275, 1258, 1191,1178, 1135, 1123, 700 cm⁻¹; mp 142° C.

EXAMPLE 10 4-Trifluoromethyl-benzoic Acid 2,2-Dimethyl-propyl Ester

To a suspension of 4-trifluoromethylbenzoic acid (75.0 g, 394 mmol) and2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in toluene (500 mL) wasadded concentrated sulfuric acid (3.0 mL). The mixture was stirred atreflux for 4 hours, cooled to room temperature, poured into saturatedaqueous sodium carbonate (250 mL) and the layers were separated. Theorganic layer was washed with saturated aqueous sodium carbonate (250mL), and brine (100 mL), and was concentrated to give4-trifluoromethyl-benzoic acid, 2,2-dimethyl-propyl ester (102 g, 99%yield) as a yellow liquid: R_(f): 0.66 (ethyl acetate/hexanes 25/75); IR2932, 1727, 1327, 1280, 1133, 1066, 862, 775, 704 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ8.16 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.04 (s, 2H),1.04 (s, 9); ¹³C NMR (100 MHz, CDCl₃) δ26.51, 31.61, 74.72, 123.63 (q,J=272.7 HZ), 125.4, 129.9, 133.7, 134.35 (q, J=31.7 Hz), 165.35.

EXAMPLE 112-(2,2-Dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic Acid

To a solution of 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propylester (4.225 g, 16.23 mmol) in tetrahydrofuran (40 mL) was addedtriisopropylborate (9.00 mL, 39.0 mmol). The solution was cooled to −78°C. and lithium diisopropylamide (12.0 mL of a 2.0 M solution intetrahydrofuran/heptane, 24.0 mmol) was added dropwise over 5 minutes.The red solution was stirred for 30 minutes, warmed to 0° C., andquenched by the slow addition of 1N hydrochloric acid (50 mL). Themixture was allowed to warm to room temperature, stirred for 30 minutesand added to hexanes (200 mL). The layers were separated and the organiclayer was washed successively with 2N hydrochloric acid (two times with100 mL), water (100 mL), and brine (50 mL). The organic extracts weredried over magnesium sulfate, filtered, and concentrated to an oil. Thecrude product was crystallized from heptane (40 mL) to provide2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid(3.037 g, 62% yield) as a white solid: mp=159-160° C.; IR 3377 (br),2963, 1703, 1371, 1308, 1171, 1131, 794, 709 cm⁻¹; ¹H NMR (400 MHz,DMSO/D₂O) δ8.05 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.66 (s, 1H),3.94 (s, 2H), 0.95 (s, 9H); ¹³C NMR (100 MHz, DMSO/D₂O) δ26.69, 31.69,74.91, 125.29, 125.75, 128.30, 129.62, 131.98 (q, J=31.8 Hz), 136.28,142.68,166.90.

EXAMPLE 12(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid 2,2-Dimethyl-propyl Ester

A bi-phasic solution of2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid(1.72 g, 5.66 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol(1.80 g, 5.63mmol), sodium carbonate (1.82 g, 17.2 mmol), andtretrakis(triphenyl-phosphine)palladium(0) (12 mg, 0.19 mol %) intoluene (15 mL) and water (9 mL) was stirred at reflux for 100 minutes.The reaction mixture was cooled to room temperature, poured into water(40 mL) and extracted with diisopropylether (75 mL). The organicextracts were washed with brine (50 mL), treated with Darco® G-60, driedover magnesium sulfate, filtered through Celite®, and concentrated. Thecrude product was purified by chromatography on silica gel (ethylacetate/hexanes 20/80) to provide (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid2,2-dimethylpropyl ester as a white foam (2.35 g, 84% yield): R_(f):0.32 (ethyl acetate/hexanes25/75); IR 3407 (br), 2961, 1721, 1336, 1292,1252, 1172, 1134, 1110, 1022, 848, 749 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.19-7.37(m, 6H), 6.88-6.93 (m, 2H), 4.53 (t,J=4.4 Hz, 1H), 4.22 (dd, J=11.2, 2.5Hz, 1H), 3.99 (dd, J=11.2, 3.3 Hz, 1H), 3.78 (s, 2H), 2.73 (dd, J=13.8,6.3 Hz, 1H), 2.54 (dd, J=13.6, 9.4 Hz, 1H), 2.20-2.80 (m, 1H), 1.81 (d,J=5.2 Hz, 1H), 0.74 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ26.64, 30.96,34.62, 41.53, 64.76, 67.42, 75.33, 116.77, 121.07, 122.97, 124.13,126.44, 127.50, 127.54, 128.45, 128.60, 128.92, 129.11, 130.25, 130.31,139.08, 141.69, 142.03, 154.44, 168.14.

EXAMPLE 13(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid

A solution of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid 2,2-dimethyl-propyl ester (2.34 g, 4.69 mmol) in isopropyl alcohol(23 mL) was treated with 10% aqueous sodium hydroxide (2.3 mL, 6.4 mmol)and heated at reflux for 3 hours. The reaction mixture was cooled toambient temperature, poured into water (34 mL), and extracted withhexanes (23 mL) and isopropyl ether (13 mL). The aqueous layer wasseparated and extracted with hexanes (23 mL) and isopropyl ether (13mL), adjusted to pH 2 with 6N aqueous hydrochloric acid, and extractedwith ethyl acetate (two times 40 mL). The combined ethyl acetateextracts were washed with brine (40 mL), dried over magnesium sulfate,filtered and concentrated to a white foam which was recrystallized fromtoluene/hexanes. The resulting solids were filtered and washed withhexanes, and the wet cake was stirred with hexanes (20 mL) for 1 hour.The mixture was filtered, and the resulting solids were dried undervacuum to provide 1.01 g (50% yield) of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid as a white solid: ¹H NMR (400 MHz, CDCl₃) δ8.00 (d, J=8.1 Hz, 1H),7.67 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), 6.91 (dd,J=7.9, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24 (dd,J=11.2, 2.7 Hz, 1H), 3.97 (dd, J=11.0, 4.0 HZ, 1H), 2.76 (dd, J=13.9,6.4 Hz, 1H), 2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).

EXAMPLE 14 2-[1,3,6,2]Dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl Ester

To a solution of 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propylester (35.8 g, 138 mmol) in tetrahydrofuran (250 mL) was addedtriisopropylborate (73.0 mL, 316 mmol). The solution was cooled to 0°C., lithium diisopropylamide (73.0 mL of a 2.0 M solution intetrahydrofuran/heptane, 146.0 mmol) was added dropwise over 20 minutes,and the red solution was stirred for an additional 30 minutes. Hexanes(200 mL) was added followed by 1N hydrochloric acid (200 mL). Themixture was stirred for 10 minutes and poured into hexanes (200 mL). Theorganic layer was washed with 1 N hydrochloric acid (two times 150 mL),and brine (100 mL). The organic extracts were dried over magnesiumsulfate, filtered, and concentrated to about 200 mL. Isopropyl alcohol(100 mL), and diethanolamine (15.95 g, 151.7 mmol) were added, and themixture was stirred at room temperature for 10 hours. The solids werefiltered and washed with a mixture of isopropyl alcohol (15 mL) andhexanes (30 mL) to provide2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester (37.83 g, 74% yield) as a white solid.mp=233-234° C.; IR 3077, 2963, 2862, 1722, 1480, 1467, 1371, 1331, 1298,1290, 1279, 1254, 1161, 1117, 1108, 1087, 1074, 995, 952, 862, cm⁻¹; ¹HNMR (400 MHz, CDCl₃) d 8.23(s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.52 (dd,J=7.9, 1.3 Hz, 1H), 6.33 (brs, 1H), 4.08-4.14 (m, 2H), 3.98 (s, 2H),3.93-3.98 (m, 2H), 3.42-3.50(m, 2H), 2.88-2.94(m, 2H), 1.02 (s, 9H); ¹³CNMR (100 MHz, CDCl₃) 26.51, 31.69, 50.92, 63.33, 74.72, 123.94, 128.59,132.06, 139.61, 171.56.

EXAMPLE 15(3S,4R)-Dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoate

A mixture of 2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoicacid 2,2-dimethyl-propyl ester (7.04 g, 18.9 mmol) in toluene (45 mL)and 1.5 N hydrochloric acid (45 mL) was stirred at room temperature for45 minutes. The aqueous layer was removed and sodium carbonate (2.73 g,25.8 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (5.47 g, 17.1 mmol),tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 20.8, μmol), andwater (20 mL) were added. The bi-phasic solution was stirred at refluxfor 100 minutes, cooled to room temperature, and poured into water (50mL). The layers were separated, and the organic layer was treated withDarco®G-60, filtered, and concentrated. The crude ester was dissolved inisopropyl alcohol (80 mL) and 10% aqueous sodium hydroxide (8.0 mL) wasadded. The solution was heated at reflux for 3 hours, cooled to roomtemperature, poured into water (120 mL), and extracted with hexanes (80mL) and isopropyl ether (40 mL). The aqueous layer was washed withhexanes (80 mL) and isopropyl ether (40 mL), adjusted to pH 2 with 6 Nhydrochloric acid, and extracted with methyl tert-butyl ether (two times75 mL). The organic extracts were dried over magnesium sulfate,filtered, and concentrated. The crude product was dissolved in methyltert-butyl ether (40 mL), and dicyclohexylamine (4.10 mL, 20.6 mmol) wasadded. The mixture as stirred overnight, and the solid was filtered andwashed with methyl tert-butyl ether (20 mL) to afford(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoate(7.32 g, 70% yield): mp=209-210° C.; IR 3307, 3025, 2939, 2858, 1626,1564, 1429, 1398, 1388, 1333, 1168, 1119, 903, 875, 846, 838 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ7.62 (d, J=7.7 Hz, 1H), 7.55 (s, 1H), 7.52 (d,J=7.9 Hz, 1H), 7.17-7.31 (m, 6H), 7.08 (dd, J=7.9, 1.7 Hz,1H), 7.00 (d,J=1.7 Hz, 1H), 4.48 (d, J−4.4 Hz, 1H), 4.17 (dd, J=11.0, 2.6 Hz, 1H),3.90 (dd, J=11.0, 5.0 Hz, 1H), 2.74-2.79 (m, 3H), 2.50 (dd, J=13.8, 9.4Hz, 1H), 1.80-1.82 (m, 4H), 2.20 (brs, 1H), 1.68-1.70 (m, 4H), 1.56 (d,J=12.2 Hz, 2H), 1.00-1.26 (m, 10H), ¹³C NMR (100 MHz, CDCl₃) δ24.70,24.73, 25.03, 28.94, 29.09, 34.75, 41.75, 52.64, 65.00, 67.57, 116.50,121.42, 122.59, 123.77, 126.38, 126.73, 128.03, 128.55, 129.06, 129.45,138.95, 139.16, 142.51, 144.20, 154.04, 173.85.

EXAMPLE 16(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid

A mixture of(3S,4R-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoate(2.37 g, 3.89 mmol) in ethyl acetate (25 mL), and 1 N hydrochloric acid(25 mL) was stirred at room temperature for 1 hour. The mixture waspoured into ethyl acetate (20 mL) and the aqueous layer was removed. Theorganic layer was washed with water (six times 50 mL), dried overmagnesium sulfate, filtered, and concentrated to provide(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid (1.66 g, 100% yield): ¹H NMR (400 MHz, CDCl₃) δ8.00 (d, J=8.1 Hz,1H), 7.67 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), (dd,J=7.9,1.7 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.2(dd, J=11.2, 2.7 Hz, 1H), 3.97 (dd, J=11.0, 4.0 Hz, 1H), 2.76 (dd,J=13.9, 6.4 Hz, 1H), 2.53 (dd, J=13.7,9.3 Hz, 1H), 2.24-2.26 (m, 1H).

EXAMPLE 17[[3(2R,3R)]-4R,5S]-3-[2-Benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one

To a solution of(4R,5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1.50g, 4.8 mmol) in dichloromethane (23 mL) at −70° C. was added titaniumtetrachloride (0.6 mL, 5.3 mmol) giving a yellow-orange solution whichwas stirred for 15 minutes at −70° C.N,N,N′,N′-Tetramethylethylenediamine(2.2 mL, 15 mmol) was added over 10minutes giving a dark red reaction mixture which was stirred for 70minutes at −78° C. 1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) wasadded dropwise, and the reaction mixture was stirred for 30 minutes at−70° C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol)in dichloromethane (5 mL) was added dropwise while maintaining areaction temperature of less than or equal to −68° C. The reactionmixture was stirred at −70° C. for 60 minutes and then allowed to warmto 0° C. over 90 minutes, at which point it was quenched with 15 mL ofsaturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixturewas stirred overnight at room temperature and filtered. The phases wereseparated and the organic phase was washed three times with water andonce with brine, dried over magnesium sulfate, and concentrated undervacuum to 2.76 g of an oil containing the title compound and 1.2equivalents of 1-methyl-2-pyrrolidinone: ¹H NMR (400 MHz, CDCl₃) δ7.48(t, J=8.1 Hz, 1H), 7.09-7.34 (m, 12H), 5.35 (d, J=7.3 Hz, 1H), 5.32 (d,J=4.9 Hz, 1H), 4.89-4.92 (m, 1H), 4.51-4.55 (m, 1H), 3.65 (bs, 1H), 3.35(dd, J=7.1, 7.1 Hz, 2H), 3.03-3.06 (m,2H), 2.81 (s, 3H), 2.34 (dd,J=8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3H).

What is claimed is:
 1. A compound of the formula

wherein R³ is selected from the group consisting of H, fluoro, chloro,C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl, phenylsulfonyl, and—S(O)_(n)(C₁-C₆ alkyl) wherein n is 0 to 2, and wherein said alkylgroup, the alkyl moiety of said alkoxy and —S(O)_(n)(C₁-C₆ alkyl)groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonylgroups are optionally substituted by 1 to 3 fluoro groups; R⁴ is C₁-C₆alkyl; and, R⁷ is C₁-C₆ alkyl.
 2. A compound of the formula

wherein R³ is selected from the group consisting of H, fluoro, chloro,C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl, phenylsulfonyl, and—S(O)_(n)(C₁-C₆ alkyl) wherein n is 0 to 2, and wherein said alkylgroup, the alkyl moiety of said alkoxy and —S(O)_(n)(C₁-C₆ alkyl)groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonylgroups are optionally substituted by 1 to 3 fluoro groups; and, R⁴ isC₁-C₆ alkyl.
 3. A compound of the formula

wherein the dashed line indicates a bond or no bond between the B and Natoms; n and m are independently 2 to 5; R³ is selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆ alkyl) wherein n is0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxyand —S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁴ is C₁-C₆ alkyl; and, R⁸ is H or C₁-C₆ alkyl.